Gut microbiota–immune crosstalk in childhood and adolescent obesity: mechanistic insights and therapeutic potential focused on short-chain fatty acids and emerging metabolites
1University-Town Hospital of Chongqing Medical University, Chongqing, China
2Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing, China
3Oncology Hematology Department, University-Town Hospital of Chongqing Medical University, Chongqing, China
4Department of Clinical Laboratory, University-Town Hospital of Chongqing Medical University, Chongqing, China
*Correspondence: Jing Shang, diciyu@163.com; Jianjiang Xue, 1208456960@qq.comAbstract
Childhood and adolescent obesity should not be explained only as a problem of eating too much energy and using too little energy. Research now shows that obesity in young people is also linked to changes in gut bacteria, changes in the way the body uses energy, and long-term mild inflammation during key stages of growth. Acting as a central metabolic nexus, the gut microbiota converts dietary substrates into short-chain fatty acids (SCFAs) along with a broad spectrum of other functional metabolites that shape the microbiota–immune–obesity axis. This review focuses on how SCFAs affect intestinal immunity, how they may be involved in innate immune training, and how they may help promote heat production in fat tissue. These effects are mainly related to the activation of cell receptors called G protein-coupled receptors (GPCRs) and the inhibition of histone deacetylase (HDAC). We further clarify the contributions of several emerging classes of metabolites: aromatic amino acid (AAA) catabolites that affect intestinal barrier integrity and mucosal inflammation; secondary bile acids that modulate energy metabolism through farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5); and N-acyl amides that act on endocannabinoid-like pathways to adjust appetite. Based on these insights, we propose a three-level intervention strategy focused on microbial metabolites—upstream reshaping of beneficial communities using prebiotics and high-fiber dietary patterns, midstream development of pediatric-specific SCFA formulations and targeted metabolite supplements, and downstream exploration of receptor-targeted pharmacotherapy. Future advances rely on integrated multi-omics designs, rigorous causal evidence from human studies, and development-appropriate personalized regimens, which will ultimately create new precision pathways for the prevention and treatment of early-life obesity.
1Introduction
The reciprocal crosstalk between gut microbiota and the host relies predominantly on diet-derived bioactive metabolites. These metabolites can act as signaling molecules that influence intestinal immune activity, systemic energy metabolism, and inflammatory responses (Bäckhed et al., 2005; Zhou et al., 2023). In childhood and adolescent obesity, alterations in gut microbial composition and function can reshape the type and abundance of microbial metabolites, particularly short-chain fatty acids (SCFAs), bile acid derivatives, and amino acid catabolites (Jiang et al., 2025). These changes may link gut microbial imbalance with long-term mild inflammation and problems in whole-body metabolism (Zhang and Dang, 2022; Yu Z. J. et al., 2023; Cho, 2023). Therefore, this review focuses on the “metabolite–microbiota–immune” axis to better understand how pediatric obesity develops and how future interventions may be designed based on biological mechanisms.
1.1Reconsidering childhood and adolescent obesity: puberty as an immune-metabolic susceptibility window beyond energy imbalance
Childhood obesity has often been explained as the result of taking in more energy than the body uses (Baranowski and Motil, 2021; Verduci et al., 2021a). However, this energy-balance model alone cannot fully explain why obesity during childhood and adolescence is strongly associated with persistent low-grade inflammation, insulin resistance, pubertal abnormalities, and later metabolic complications (Cho, 2023; Mindru et al., 2025). A more development-oriented interpretation is therefore needed, in which pediatric obesity is viewed not only as excessive fat accumulation but also as an immune-metabolic disorder occurring during a period of rapid growth and physiological remodeling. Puberty represents a particularly sensitive window for obesity-related immune and metabolic dysregulation. During this stage, sex hormones, growth hormone, insulin sensitivity, adipose tissue distribution, and immune maturation change rapidly (Huang and Roth, 2021; Carson et al., 2023). These developmental changes may amplify the inflammatory consequences of excess adiposity, making adolescents more vulnerable to chronic low-grade inflammation than would be predicted by body weight alone. In this context, gut microbiota and microbial metabolites should be understood as modulators of pubertal inflammatory susceptibility rather than as isolated descriptive markers. During childhood and adolescence, the gut microbiota and the immune system are still developing at the same time. Diet, daily habits, and environmental factors, such as antibiotic use and not getting enough sleep, can easily affect the balance of gut bacteria. These factors may also change the metabolite environment in the gut and lead to immune and inflammatory responses (Vallianou et al., 2021; Gunawan et al., 2024). Several pediatric cohorts have reported reduced microbial diversity and altered abundances of beneficial bacteria, including Akkermansia muciniphila, and Faecalibacterium prausnitzii, in children and adolescents with obesity. However, these findings are not consistent across all populations, and the direction or magnitude of these microbial changes may vary according to ethnicity, geography, diet, age, pubertal status, metabolic phenotype, and sequencing methodology (de Cuevillas et al., 2022; Yuan et al., 2021a; Murga-Garrido et al., 2022). These changes are also linked with higher serum levels of tumor necrosis factor-α, also called TNF-α, and interleukin-6, also called IL-6. Together, these changes may form a cycle in which gut bacterial imbalance, metabolic problems, and inflammation affect each other (Yuan et al., 2021a; Burananat et al., 2025; Newman et al., 2023). Observational studies and Mendelian randomization studies also suggest that gut dysbiosis may help cause obesity, rather than only appearing after obesity has already developed (Li et al., 2024; Lu et al., 2024). The pubertal inflammatory-susceptibility framework is also relevant to metabolic remodeling. Pubertal obesity is closely associated with insulin resistance and abnormal sexual development, suggesting multisystem dysregulation beyond caloric excess (Huang and Roth, 2021; Qian et al., 2024). Hormonal changes during puberty may alter gut barrier integrity and increase vulnerability to microbial lipopolysaccharide (LPS) translocation, thereby promoting systemic inflammatory responses (Li et al., 2021). At the same time, obesity-related branched-chain amino acid (BCAA) accumulation should be interpreted as a multifactorial metabolic alteration influenced by dietary intake, hepatic and muscle metabolism, insulin resistance, and gut microbial BCAA transport or metabolism, rather than as a microbiota-driven change alone (Moran-Ramos et al., 2021; Yuan et al., 2023; Del Chierico et al., 2021). These mechanisms may jointly worsen insulin resistance, adipose tissue inflammation, and lipid storage during adolescence. These pubertal-specific vulnerabilities, when combined with dysbiosis-driven inflammation, also predispose affected individuals to comorbid conditions such as metabolic-associated fatty liver disease and metabolic syndrome (Rohani et al., 2025; Wierzbicka-Rucinska et al., 2025). Collectively, these findings support reconceptualizing childhood and adolescent obesity as a disorder rooted in disrupted gut microbiota–metabolism–immune crosstalk, superimposed upon a background of pubertal chronic inflammatory susceptibility (Fiore et al., 2023). This ecological perspective—shifting the focus from isolated energy balance to network-level dysregulation—offers a new framework for understanding the pathogenesis of pediatric obesity. Figure 1 shows the main differences between healthy conditions and obesity conditions in gut microbiota composition, intestinal barrier function, and immune-inflammatory status.
1.2The gut microbiota as a signal converter that changes dietary substrates into bioactive metabolites
Childhood and adolescence are important periods for the development of gut microbiota, with lasting implications for metabolism and immune function (Carson et al., 2023; Jian et al., 2021). The gut microbiota functions as a metabolic converter, by transforming dietary components into small active molecules, especially SCFAs, bile acids, and indole derivatives (Zhou et al., 2023; Fiore et al., 2022; Koller et al., 2025). Diet directly modulates this process. High-energy, low-fiber dietary patterns reduce microbial diversity and disrupt gut microbial function. Diets rich in complex carbohydrates may help maintain a gut environment that supports better metabolism (Bagheri et al., 2022; Orbe-Orihuela et al., 2022). Thus, the types of gut bacteria microbial composition and metabolic capacity determine how dietary inputs are converted into host-sensed chemical signals (Arnoldini et al., 2025; Yu et al., 2025).
When this signaling pathway is disrupted, it plays a critical role in obesity among children and adolescents: some beneficial metabolic pathways are downregulated, while certain harmful pathways become overactive, collectively altering the overall metabolite profile (Del Chierico et al., 2021; Murga-Garrido et al., 2023; Squillario et al., 2023). These metabolites influence gut hormone release, immune cell activity, and whole-body energy balance. They may do this by interacting with receptors such as G protein-coupled receptor 41 (GPR41) and G protein-coupled receptor 43 (GPR43). They may also weaken the intestinal barrier, which can lead to long-term mild inflammation and metabolic problems (Koller et al., 2025; Klag et al., 2026; Li S. et al., 2025). Diet is one of the main factors that controls this process. Higher intake of ultra-processed foods is associated with reduced SCFA production and increased pro-inflammatory products. A high-fiber diet may support the production of anti-inflammatory metabolites (Calcaterra et al., 2023; Deligeorgopoulou et al., 2025; Ouradova et al., 2025). This metabolic function is not the same in every person or every population. Obesity-related gut microbiota patterns have also been reported in specific groups, including Chinese and Mexican cohorts (Murga-Garrido et al., 2022; Balakrishnan et al., 2021; Li et al., 2022). Childhood and adolescent obesity can therefore be understood as a problem linked to abnormal signals from the gut microbiota. Studying these disturbed functional patterns may help explain how diet, gut microbiota, and the host affect each other, and supports the development of more targeted intervention strategies (Zhang and Dang, 2022; de Cuevillas et al., 2022).
2Core regulatory mechanisms of SCFAs in childhood and adolescent obesity
2.2SCFAs in the regulation of local gut immunity
SCFAs are key signals maintaining intestinal immune homeostasis in children and adolescents, acting through GPCRs and HDAC inhibition (Jiang et al., 2025; Akagbosu et al., 2022; Agustina et al., 2025).
Within the GPCR axis, GPR43 is broadly expressed on lymphoid tissues and immune cells. SCFAs binding to GPR43 dampens pro-inflammatory cascades such as the nuclear factor kappa B (NF-κB) pathway, reducing TNF-α and IL-6 secretion while promoting Treg differentiation (Newman et al., 2023). G-protein-coupled receptor 109A (GPR109a), mainly activated by butyrate and highly expressed on intestinal macrophages, drives apoptosis of inflammatory cells and upregulates the anti-inflammatory cytokine interleukin-10 (IL-10; Akagbosu et al., 2022; Agustina et al., 2025). In the HDAC arm, SCFAs enter the nucleus, inhibit HDAC activity, and induce histone hyperacetylation, which activates the transcription of anti-inflammatory cytokines and silences pro-inflammatory genes, further enforcing an anti-inflammatory phenotype (Zhang and Dang, 2022; Fiore et al., 2022). At the cellular level, these pathways work together to push macrophages toward the anti-inflammatory M2 phenotype and limit M1 polarization. This effect is partly related to macrophage metabolic reprogramming caused by HDAC inhibition. Although such mechanisms have been linked to improved insulin sensitivity and reduced hepatic lipid accumulation in experimental models, direct clinical evidence in children remains limited (Newman et al., 2023; Del Chierico et al., 2021; Czarnowski et al., 2023). SCFAs also control excessive neutrophil activation through GPR43, including chemotaxis, reactive oxygen species production, and apoptosis. This helps reduce intestinal tissue damage and keeps the epithelial barrier intact (Zhou et al., 2023; Deligeorgopoulou et al., 2025; Pînzariu et al., 2025).
In pediatric obesity, gut dysbiosis can lower SCFA production and weaken these immune-regulating brakes. When SCFA-related control of NF-κB suppression and HDAC-driven transcriptional regulation becomes weaker, TNF-α and IL-6 production can increase. At the same time, weaker control of macrophage M1/M2 polarization and continued neutrophil activation can worsen tissue damage and compromise the epithelial barrier (Fiore et al., 2022; Li S. et al., 2025; Pînzariu et al., 2025). Overall, impaired SCFA-mediated local immune regulation may contribute to epithelial barrier dysfunction and chronic low-grade intestinal inflammation, which can interact with systemic metabolic abnormalities (Newman et al., 2023; Li et al., 2024).
SCFAs are also important for building and maintaining the intestinal epithelial barrier. Butyrate serves as the main energy source for colonocytes. It supports cell proliferation, cell differentiation, and mucosal homeostasis (Pînzariu et al., 2025). SCFAs also suppress HDACs to enhance the expression of tight-junction genes and interact with GPR43/GPR109a to facilitate barrier protein synthesis through the mitogen-activated protein kinase (MAPK)/phosphatidylinositol 3-kinase (PI3K)-Akt pathway; acetate and butyrate, for example, significantly elevate zonula occludens-1 (ZO-1) and occludin levels, strengthening the physical barrier (Fiore et al., 2022; Akagbosu et al., 2022; Pi et al., 2024). Additionally, SCFAs help stabilize hypoxia-inducible factor, stimulate intestinal trefoil factor to speed up mucosal repair, and attenuate NOD-like receptor protein 3 (NLRP3) inflammasome activation (Akagbosu et al., 2025; Agustina et al., 2025).
In obesity, reduced SCFA production can leave the epithelium with less energy and make tight junctions looser. This raises intestinal permeability and makes it easier for LPS to move across the gut barrier, a process known as metabolic endotoxemia (Zhang and Dang, 2022). LPS then activates Toll-like receptor 4 (TLR4) and NF-κB pathways, inducing TNF-α and IL-6 release and triggering systemic chronic low-grade inflammation that connects gut dysbiosis to insulin resistance and fat accumulation (Fiore et al., 2022; Akagbosu et al., 2025; Ahmed et al., 2021). However, evidence that SCFA-targeted interventions directly prevent long-term metabolic sequelae in children remains limited. Current pediatric data mainly support the potential of fiber or prebiotic strategies to reshape the microbiota–metabolite environment and improve selected metabolic indices, rather than proving direct disease-modifying effects of SCFAs themselves (Mo et al., 2025; Visuthranukul et al., 2024b). Figure 2 outlines the multi-functional effects of SCFAs on immune cell function, adipose tissue thermogenesis, and gut barrier integrity.
2.3Integrated regulation of systemic immunity and metabolism by SCFAs
During childhood and adolescence, butyrate and propionate are absorbed through the portal vein and help form a gut–systemic immune regulatory axis. Experimental studies suggest that SCFAs may influence immune cell differentiation through HDAC inhibition and GPCR-related signaling, including effects on Treg differentiation and myeloid cell polarization (Jiang et al., 2025; Newman et al., 2023; Akagbosu et al., 2025). However, the concept of SCFA-mediated “immune training” in humans, especially in children and adolescents, remains largely inferential and should be interpreted cautiously. Immune cells influenced by SCFA-related signaling may also affect peripheral tissues, including adipose tissue. In experimental models, SCFAs have been associated with reduced M1 macrophage polarization, increased M2-like macrophage features, and enhanced Treg-related anti-inflammatory responses in adipose tissue (Li et al., 2024; Akagbosu et al., 2025; Ahmed et al., 2021). In humans, however, direct evidence that SCFAs induce durable immune training and thereby remodel adipose tissue immunity during pediatric obesity remains limited. These anti-inflammatory effects may reduce the release of TNF-α and IL-6 and increase anti-inflammatory mediators such as IL-10 and adiponectin, but the extent to which this pathway operates in children with obesity requires further validation.
SCFAs also act as vital signaling molecules within the gut–adipose axis, orchestrating comprehensive modulation of adipose tissue energy metabolism and phenotypic remodeling. On one hand, they activate GPR41/43 on adipocytes, suppressing transcription of sterol regulatory element-binding protein 1c (SREBP-1c) and increasing the activity of lipolytic enzymes such as lipoprotein lipase, thereby restricting triglyceride accumulation in white adipose tissue (WAT). Meanwhile, they improve the immune milieu by blocking pro-inflammatory activation of macrophages (Newman et al., 2023; Al-Daghri et al., 2021; Akagbosu et al., 2022). On the other hand, experimental studies also suggest that SCFAs may regulate adipose tissue thermogenic programs by increasing the expression of thermogenic genes such as uncoupling protein 1 (UCP1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and by engaging pathways related to peroxisome proliferator-activated receptor gamma (PPARγ)/PGC-1α and β3-adrenergic receptor (β3-AR)/p38 mitogen-activated protein kinase (p38 MAPK) signaling (Al-Daghri et al., 2021; Alcázar et al., 2022). However, whether SCFAs directly drive beige adipocyte generation through this pathway in humans remains uncertain, and pediatric evidence is particularly limited. SCFAs also strengthen the adipose thermogenic program by activating gut–brain sympathetic circuits (Verduci et al., 2021b). Since children and adolescents have relatively more BAT than adults, SCFA-mediated thermogenesis may be especially important for weight regulation during puberty, although this remains largely extrapolated from animal data (Alcázar et al., 2022). In obesity, gut dysbiosis alters SCFA profiles and contribute to impaired adipose tissue metabolic regulation, but the extent to which this pathway directly causes adipose tissue-specific insulin resistance in humans requires further validation (Jardon et al., 2025). Although reduced BAT activity is bidirectionally linked to obesity-related complications such as non-alcoholic fatty liver disease (NAFLD; Ahmed et al., 2021). Despite these promising preclinical findings, SCFAs have attracted considerable translational interest as a potential “metabolic switch” that activates BAT and induces WAT browning (Verduci et al., 2021b). Accordingly, dietary strategies such as fiber and prebiotics that remodel the microbiota metabolite landscape and optimize SCFA production and composition may help improve SCFA-related metabolic signaling, offering novel targets for preventing and treating obesity and metabolic syndrome in the young (Al-Daghri et al., 2021; Alcázar et al., 2022). The biological effects exerted by SCFAs through distinct receptors and pathways, together with their functional impairments in obesity, are summarized in Figure 3 and Table 2.
| Regulatory dimension/tissue system | Obesity-related alteration | Core receptor targets | Functional interpretation | Evidence basis and translational limitation | References |
|---|---|---|---|---|---|
| Gut local immunity | Altered SCFA availability or signaling may weaken NF-κB suppression and HDAC-associated anti-inflammatory regulation; macrophage M1/M2 balance, Treg responses, and neutrophil activation may be affected. | GPR43, GPR109a, HDAC; NF-κB, IL-10-related signaling, and histone acetylation. | Supports local immune homeostasis and may limit excessive TNF-α/IL-6 production and epithelial inflammatory injury. | Mechanistic evidence is strong in cell and animal studies. Pediatric human evidence mainly supports associations between SCFA-related dysbiosis and inflammatory phenotypes, not definitive causality. | Newman et al., 2023; Li et al., 2024; Del Chierico et al., 2021; Fiore et al., 2022; Czarnowski et al., 2023; Akagbosu et al., 2022; Agustina et al., 2025; Pînzariu et al., 2025 |
| Gut epithelial barrier integrity | Reduced butyrate availability or altered SCFA signaling may compromise colonocyte energy supply, tight-junction support, and mucosal repair. | GPR41, GPR43, GPR109a, HDAC; MAPK/PI3K-Akt; HIF and trefoil factor-related pathways; autophagy-related stress responses and NLRP3 inflammasome modulation. | May increase intestinal permeability and facilitate LPS translocation, contributing to metabolic endotoxemia. | Barrier effects are supported by experimental and mechanistic evidence. Direct pediatric clinical evidence that SCFA-targeted interventions prevent long-term metabolic complications remains limited. | Zhang and Dang, 2022; Fiore et al., 2022; Akagbosu et al., 2025, 2022; Pînzariu et al., 2025; Pi et al., 2024 |
| Developmental immune training | SCFA-related signals may influence developing immune-cell differentiation, but durable “immune training” in humans should not be assumed. | HDAC inhibition and GPCR signaling affecting Treg differentiation, myeloid cell polarization, and inflammatory gene transcription. | May contribute to immune tolerance and lower inflammatory tone. This should be described as immune modulation rather than confirmed immune training in pediatric humans. | Mainly experimental and mechanistic evidence. Direct evidence for long-lasting SCFA-mediated immune training in children and adolescents is limited. | Jiang et al., 2025; Carson et al., 2023; Newman et al., 2023; Arnoldini et al., 2025; Akagbosu et al., 2025 |
| Adipose tissue metabolism | Altered SCFA signaling may influence adipocyte lipid handling and thermogenic programs, but direct beige adipocyte generation in humans is uncertain. | GPR41, GPR43, HDAC; SREBP-1c, lipolytic enzymes, UCP1, PGC-1α, PPARγ/PGC-1α, and β3-AR/p38 MAPK-related signaling. | Potential effects include reduced triglyceride accumulation and increased thermogenic gene expression in experimental models. Human BAT activation and WAT browning remain less certain. | Evidence for β3-AR/p38 MAPK-mediated beige adipocyte generation comes mainly from cell and animal models. Pediatric validation is particularly limited. | Jardon et al., 2025; Al-Daghri et al., 2021; Akagbosu et al., 2022; Ahmed et al., 2021; Alcázar et al., 2022; Verduci et al., 2021b |
| Gut-brain axis regulation | Altered SCFA profiles may reduce gut hormone responses and contribute to appetite dysregulation, but responses vary according to diet, baseline microbiota, and host metabolism. | GPR41/GPR43-mediated PYY and GLP-1 secretion; vagal and hypothalamic appetite pathways. | May influence satiety signaling and energy intake as part of the gut-brain axis. | Supported by mechanistic and human association/intervention evidence to varying degrees. Direct pediatric clinical efficacy remains context-dependent. | Yu et al., 2025; Klag et al., 2026; Liang et al., 2021; Visuthranukul et al., 2024a; Panichsillaphakit et al., 2025 |
| Integrated systemic metabolic outcomes | SCFA-related barrier, immune, adipose, and gut-brain pathways may interact with insulin resistance, hepatic lipid accumulation, and metabolic syndrome. | Combined GPCR/HDAC signaling; endotoxemia-TLR4/NF-κB axis; adipose inflammatory signaling; gut hormone pathways. | Provides an integrated mechanistic framework linking gut microbial metabolites with systemic metabolism. | Should be presented as biologically plausible and partially supported by experimental and observational evidence, not as a clinically established SCFA-driven therapeutic mechanism in children. | Zhang and Dang, 2022; Newman et al., 2023; Li et al., 2024; Jardon et al., 2025; Al-Daghri et al., 2021; Akagbosu et al., 2025; Pînzariu et al., 2025; Ahmed et al., 2021; Alcázar et al., 2022; Verduci et al., 2021b |
3Unique mechanisms of novel microbial metabolites in childhood and adolescent obesity
Beyond SCFAs, the gut microbiota generates a broad spectrum of structurally distinct bioactive compounds from host-derived and dietary substrates, predominantly aromatic amino acid (AAA) metabolites, secondary bile acids and N-acyl amides. These molecules help regulate energy balance, immune balance, and glucose and lipid metabolism through direct or indirect signaling pathways. This provides new understanding of how childhood and adolescent obesity develops (Wei et al., 2023; Jaimes et al., 2021; Andriyas et al., 2025).
3.3N-acyl amides: regulation of appetite and inflammation via G protein-coupled receptors
Structurally similar to the body's own endocannabinoids, gut microbiota-derived N-acyl amides work as lipid signaling molecules. They help regulate energy balance and immune metabolism in children and adolescents by binding to GPCRs and classical cannabinoid receptors 1/2 (CB1/CB2; Zhou et al., 2023; Jiang et al., 2025; Wei et al., 2023). Their production is closely related to dietary fat and carbohydrate intake. Under obese conditions, dysbiosis can lead to abnormal accumulation of N-acyl amides, which is associated with adolescent hyperphagia and fat deposition (Wei et al., 2023; Andriyas et al., 2025).
In appetite regulation, N-acyl amides have two different effects through the gut–brain axis. They activate G protein-coupled receptor 119 (GPR119) on intestinal enteroendocrine cells and stimulate the secretion of satiety hormones, including GLP-1 and PYY. This helps limit food intake (Liang et al., 2021; Cheng et al., 2024). At the same time, certain subtypes bind to hypothalamic CB1, increase appetite drive, and form a vicious cycle of dysbiosis, metabolite abnormality, and energy accumulation. They also reduce lipolysis and promote lipid deposition through G-protein-coupled receptor 10 (GPR10; Wei et al., 2023; Al-Daghri et al., 2021; Aragón-Vela et al., 2021).
Beyond appetite, N-acyl amides also affect metabolic and immune balance through other pathways. In adipose tissue, they activate the PPARα pathway, which promotes fatty acid oxidation and improves insulin sensitivity (Cao et al., 2025). Within the intestinal immune microenvironment, engagement of CB2, G-protein-coupled receptor 55 (GPR55), and G-protein-coupled receptor 18 (GPR18) on immune cells modulates the release of pro-inflammatory cytokines such as TNF-α and IL-6. This helps reduce obesity-related chronic low-grade inflammation (Newman et al., 2023; Li et al., 2024; Cheng et al., 2024). Notably, the gut commensal Faecalibacterium prausnitzii expresses fatty acid amide hydrolase (FAAH), which carefully regulates local N-acyl ethanolamine levels and keeps a dynamic balance between immune and energy sensing (Klag et al., 2026). Given that the endocannabinoid system is not fully developed in children and adolescents, abnormal N-acyl amide accumulation can further destabilize metabolic regulation. Antagonists or inhibitors targeting GPR119 and CB1 represent promising strategies for precision intervention. Even so, their safety and long-term efficacy in the young require clinical assessment (Al-Daghri et al., 2021; Aragón-Vela et al., 2021).
The unique pathways through which these novel microbial metabolites participate in the microbiota–immune–obesity dialogue are summarized in Table 3. Evidence categories were used to distinguish experimentally validated mechanisms, pediatric observational associations, randomized or non-randomized clinical intervention evidence, and emerging hypotheses lacking direct pediatric therapeutic validation. Changes in the abundance and metabolic contributions of key functional bacterial groups are shown in Table 4, and the main pathways and targets of different microbial metabolite classes in childhood and adolescent obesity are illustrated in Figure 4.
| Metabolite category | Representative molecule | Mainly produced by bacterial genera | Abnormal under obese conditions | Core receptor target | Regulatory effect on obesity | Evidence type and validation status | References |
|---|---|---|---|---|---|---|---|
| AAAs | 4-HPAA | Flavonifractor plautii | Fecal and serum 4-HPAA concentrations markedly reduced. | Likely through GPR43, activating PI3K/Akt. | Activating ILC3s boosts IL-22 secretion and strengthens the gut barrier; downregulating intestinal fat-absorption proteins cuts fat accumulation. | Experimental mechanistic evidence plus pediatric association. The anti-obesity mechanism has been experimentally validated, but direct pediatric supplementation or receptor-targeted intervention has not been confirmed by randomized controlled trials. Therefore, 4-HPAA should be described as a mechanistically supported candidate rather than a clinically validated therapeutic target. | Jiang et al., 2025; Ahmed et al., 2021; Li Q. R. et al., 2025; Álvarez-Arraño and Martín-Peláez, 2021; Yin et al., 2025 |
| Indole derivatives | IPA, IAA | Bifidobacteria, Lactobacilli, etc. | Production sharply drops, tightly linked to systemic low-grade inflammation. | Aromatic hydrocarbon receptor. | AHR-related signaling may support gut barrier integrity, limit excessive NLRP3 inflammasome activation, and influence Treg/Th1/Th17 immune balance; direct pediatric therapeutic validation remains limited. | Experimental mechanistic evidence plus human metabolomic association. Pediatric observational and metabolomic studies support associations with inflammation and cardiometabolic risk, but interventional evidence in children and adolescents remains insufficient. | Rivera et al., 2025; Deng et al., 2025; Andriyas et al., 2025; Sun D. et al., 2025; Luo et al., 2025 |
| Secondary bile acid | Lithocholic acid, deoxycholic acid | Bacteroides, Clostridium | An imbalance in the bile acid pool composition is associated with MASLD and the progression of insulin resistance. | FXR, TGR5. | FXR activation regulates gluconeogenesis and lipid synthesis; TGR5 activation promotes GLP-1 secretion, enhances brown adipose tissue thermogenesis, and curbs macrophage inflammation. | Pediatric observational and multi-omics association plus established receptor biology. FXR/TGR5 signaling is biologically plausible and mechanistically supported, but bile acid receptor agonists should be regarded as translational candidates because pediatric obesity-specific safety and efficacy data remain limited. | Chan et al., 2026; Giannini et al., 2022; Wei et al., 2023; Zöggeler et al., 2025; Aragón-Vela et al., 2021; Aqeel et al., 2025; Mancera-Hurtado et al., 2023 |
| N-Acylamide | N-Acylethanolamine | Various symbiotic bacteria, with Faecalibacterium prausnitzii modulating its levels. | Abnormal accumulation of metabolic profiles is positively correlated with increased appetite and fat accumulation during puberty. | CB1, CB2, GPR119, GPR55, GPR18, PPARα. | GPR119 triggers GLP-1 and PYY secretion to suppress appetite; CB2 activation modulates immune inflammation; PPARα activation drives fatty acid oxidation. | Emerging hypothesis based mainly on indirect mechanistic and receptor-based evidence. Current evidence is insufficient to define N-acylamides as validated therapeutic targets in pediatric obesity. They should be presented as exploratory candidates requiring pediatric clinical validation. | Li et al., 2024; Klag et al., 2026; Wei et al., 2023; Al-Daghri et al., 2021; Cheng et al., 2024; Cao et al., 2025; Mora-Godínez et al., 2025; Yin et al., 2024 |
| 5-Aminovaleric acid and other metabolites (5-AVA) | 5-Aminovaleric acid | Fusobacterium mortiferum, Parabacteroides goldsteinii | Obesity is associated with elevated abundance of F. mortiferum and increased 5-AVA levels, which are tightly linked to the progression of obesity-related colorectal cancer. Pediatric obesity cohorts consistently exhibit widespread gut microbial dysbiosis and profoundly altered metabolite profiles. | Wnt/β-catenin pathway. | 5-AVA activates the Wnt/β-catenin pathway through DKK2, thereby promoting colorectal tumorigenesis in the obese state, suggesting a detrimental metabolic bridge connecting obesity to malignant transformation. However, its direct causal role in adiposity accumulation per se remains to be elucidated. Additionally, 1,4-methylimidazoleacetic acid, associated with P. goldsteinii enrichment, has been observed in the context of obesity amelioration. | Mechanistic evidence (in vivo/vitro) validates the 5-AVA/Wnt-β-catenin pro-tumorigenic axis, with pediatric metabolomic studies providing associative support. Direct interventional pediatric data are lacking, positioning 5-AVA as a mechanistically supported obesity-cancer link rather than a clinically validated therapeutic target for pediatric obesity. | Zhang and Dang, 2022; de Cuevillas et al., 2022; Granato et al., 2025; Jardon et al., 2025; Nguyen Tran et al., 2025 |
| Microbiota-modulating interventions related to metabolite output | Not a single metabolite; includes fiber-, chitosan-, metformin-, probiotic-, and lifestyle-related modulation of microbial metabolites | Depends on intervention-induced changes in SCFA-producing, tryptophan-metabolizing, bile-acid-transforming, and other functional bacteria | Interventions may partially restore dysbiotic microbiota and improve metabolite output profiles, but effects differ across individuals and developmental stages. | Indirect regulation of SCFA, aromatic amino acid-derived metabolite, bile acid, and endocannabinoid-like pathways. | These interventions support the clinical feasibility of targeting the microbiota-metabolite axis, but they do not prove that 4-HPAA, N-acylamides, or secondary bile acids themselves are validated pediatric therapeutic targets. | Randomized or non-randomized clinical intervention evidence; indirect support only. Pediatric and adolescent studies, including randomized, double-blind and pre-post dietary intervention designs, provide clinical support for microbiota modulation, but metabolite-specific causal evidence remains limited. | Mo et al., 2025; Visuthranukul et al., 2024b; Kilic Yildirim et al., 2023; Li et al., 2025; Du et al., 2025; Ayoub-Charette et al., 2023 |
| Key functional microbial communities | Abundance changes under obesity | Main metabolic contribution | Core impact on host health | References |
|---|---|---|---|---|
| Faecalibacterium prausnitzii | Significantly reduce | Produces butyric acid and synthesizes propionic acid; produces N-acylamide regulatory factors; participates in BCAA transport regulation. | Anti-inflammatory, preserves the intestinal barrier, and fine-tunes immune homeostasis—potentially improving insulin sensitivity via BCAA modulation. | Yuan et al., 2021a; Newman et al., 2023; Moran-Ramos et al., 2021; Ahmed et al., 2021 |
| Bifidobacterium | Reduce | Fermentable dietary fiber produces acetic acid and lactic acid; it participates in tryptophan metabolism to produce indole derivatives. | Maintains gut barrier, modulates immunity, suppresses pathogens, and ameliorates metabolic endotoxemia. | Agustina et al., 2025; Andriyas et al., 2025; Liang et al., 2024; Liang and Zhang, 2024 |
| Akkermansia muciniphila | Reduce | Degrades mucin to produce propionic acid and acetic acid; regulates the thickness of the intestinal mucus layer. | Enhances barrier function, reduces endotoxin translocation, improves insulin sensitivity, and exerts anti-inflammatory effects. | Yuan et al., 2021b; Becken et al., 2021; Zhang Y. et al., 2025 |
| Flavonifactor plautii | Speculative reduction | Metabolizes flavonol substances to produce 4-HPAA. | Through 4-HPAA, it activates ILC3s to strengthen the gut barrier; it downregulates intestinal fat absorption, curbing weight gain. | Jiang et al., 2025; Li Q. R. et al., 2025; Álvarez-Arraño and Martín-Peláez, 2021 |
| Roseburia | Reduce | Mainly produces butyric acid | Supplies energy to colonic epithelium, sustains the intestinal barrier, and acts anti-inflammatory. | Akagbosu et al., 2025; Vázquez-Bolea et al., 2025 |
| Eubacterium | Reduce | Produces butyric acid and participates in bile acid and cholesterol metabolism. | Preserves intestinal homeostasis, regulates host energy metabolism, and immune responses. | McCann et al., 2021 |
| Lactobacillus | Some strains decrease | Produces lactic acid and acetic acid; some strains produce conjugated linoleic acid; regulates tryptophan metabolism. | Maintains an acidic gut environment, inhibits pathogens, and regulates immunity—may influence appetite via PYY secretion. | Liang et al., 2021; Agustina et al., 2025; Aragón-Vela et al., 2021; Mogos et al., 2025 |
| Bacteroidetes and Firmicutes | Proportional imbalance | Mainly produces acetic acid and propionic acid; participates in carbohydrate and protein fermentation as well as bile acid metabolism. | Affects energy harvest; abundance closely tied to dietary fiber intake and SCFA production. | Gyarmati et al., 2021 |
| Clostridium cluster IV and XIVa | Reduce | Core butyrate-producing bacterial groups, including Faecalibacterium prausnitzii and Roseburia. | Crucial for gut health and metabolic homeostasis; their depletion correlates with multiple metabolic disorders. | Carson et al., 2023; Akagbosu et al., 2022 |
| Lachnospiraceae | Complex changes, some strains decrease | Contains various butyrate-producing bacteria, such as Roseburia; Participate in carbohydrate fermentation | Plays a key role in maintaining gut health and energy metabolism. | Akagbosu et al., 2025; Wang J. J. et al., 2024 |
| Ruminococcaceae | Reduce | Produces acetic acid and butyric acid, involved in cellulose degradation. | Regulates intestinal immune tolerance and lipid absorption; SCFA-producing capacity is diminished in obese children. | Yuan et al., 2021a; Ma et al., 2023; Mörkl et al., 2025 |
4Intervention strategies targeting microbial metabolites in childhood and adolescent obesity
Microbial metabolites—SCFAs, bile acids, AAA, and tryptophan metabolites, BCAA-related products, and trimethylamine N oxide (TMAO)—are involved in pediatric obesity-related metabolic regulation at different levels of evidence. SCFAs and selected bile acid-related signals may influence intestinal barrier function, inflammation, gut hormone secretion, lipid metabolism, and neuroendocrine pathways (Fiore et al., 2022; Koller et al., 2025; Nguyen Tran et al., 2025). Compared with simply restricting energy intake, microbiota–metabolite pathway-oriented strategies focus on the regulatory cascade of diet–microbiota–metabolites–host targets, which helps enhance personalized management and long-term adherence (Koller et al., 2025; Gawlik et al., 2021). This section categorizes relevant approaches into four major directions: upstream microbiota modulation, intermediate metabolite supplementation, downstream receptor intervention, and existing research limitations. The overall framework is presented in Figure 5.
4.1Child-adapted prebiotic, high-fiber, and Mediterranean-style dietary strategies for modulating metabolite-producing microbiota
Prebiotics promote fermentation by beneficial bacteria, boosting SCFA output and thereby regulating fat storage, insulin sensitivity, and low-grade inflammation (Zhou et al., 2023; Pînzariu et al., 2025). They serve as selective substrates that enrich SCFA producers such as Bifidobacterium and Faecalibacterium, counteracting the dysbiosis and metabolic substrate depletion characteristic of high-fat, high-sugar, low-fiber diets. This approach raises gut propionate and butyrate levels and has shown potential in proof-of-concept studies to improve body composition and metabolic markers; for example, inulin, fructooligosaccharides, and (in vitro) stachyose all modulate the microbiota and metabolites of obese children, with inulin also influencing the gut–brain axis via microbial metabolite profiles (Visuthranukul et al., 2024b; Andriyas et al., 2025; Pi et al., 2024). The resulting metabolites not only promote PYY and GLP-1 secretion to regulate appetite, but may also influence body composition through putative gut–muscle axis pathways, although this remains largely hypothetical in humans, with particularly limited evidence in pediatric populations (Visuthranukul et al., 2024a; Yu X. et al., 2023; Panichsillaphakit et al., 2025). Fiber tolerance varies; therefore, gradual dose escalation and selection of appropriate fiber types are essential to minimize bloating and pain, and attention to potential biphasic effects is warranted (Basuray et al., 2024).
Dietary pattern modification is the main way to reshape the intestinal metabolic microenvironment. Increased intake of whole grains, legumes, fruits, vegetables, and nuts provides many fermentable substrates, increases the production of SCFAs and beneficial metabolites, and limits harmful metabolic pathways. In contrast, limiting ultra-processed foods and sugar-sweetened beverages can lower metabolic risks and improve microbial metabolic profiles (Calcaterra et al., 2025, 2024; Lane et al., 2024). Practical measures, such as choosing high-fiber staple foods, selecting healthy snacks, and using family-based shopping guidance that matches children's tastes, can make the intervention easier to carry out and support long-term adherence (Aqeel et al., 2025). The Mediterranean diet, which is rich in fiber and polyphenols, supports a stable, anti-inflammatory, and metabolically resilient microbiota. It shows potential for pediatric obesity and related comorbidities and can be maintained in both home and school settings (Bagheri et al., 2022; Deligeorgopoulou et al., 2025). Such holistic dietary interventions work as long-term regulation of the gut ecosystem. They may increase microbial diversity and SCFA-related metabolic capacity through more diverse dietary fiber intake (Yu et al., 2025; Basuray et al., 2024; Yang et al., 2024). Importantly, the preventive effect of dietary fiber on childhood obesity is microbiota-dependent, underscoring the central role of the high-fiber diet–microbiota–metabolite axis (Yu et al., 2025).
Modern gut microbiota research has evolved from taxonomic profiling to function-oriented analyses focused on metabolites. Quantitative analyses reveal substantial inter-individual variation in the efficiency with which a given substrate is converted into metabolites, calling for upstream strategies that match substrate, microbial function, and metabolite output (Arnoldini et al., 2025; Gawlik et al., 2021). Prebiotic supplementation and high-fiber/Mediterranean diets are thus complementary: prebiotics are being investigated for early clinical correction of specific metabolic deficits, while high-fiber dietary patterns form the foundation for long-term health management (Cho, 2021; Zhou et al., 2024). Combined use of these approaches has the potential to ameliorate SCFA insufficiency induced by dysbiosis, and may help restore the protective effects of SCFAs in preserving mucosal integrity, regulating energy metabolism and restraining chronic low-grade inflammation (Zhang and Dang, 2022; Li S. et al., 2025). Gut microbial disturbance is generally more severe in obese children than in adults, offering a broader time frame for microbiota modulation. Meanwhile, all interventions need to fully consider age-related physiological features (Yu Z. J. et al., 2023; Carson et al., 2023). Collectively, although prebiotic interventions are conceptually attractive and supported by mechanistic plausibility, they remain predominantly at the stage of experimental investigation; large-scale pediatric efficacy and safety trials are needed before clinical translation (Wu et al., 2025; Fahim et al., 2025). To put these strategies into practice, precision metabolite-based interventions should be combined with microbiota ecosystem cultivation. This can be done through new food design and systematic nutrition education that closely fit children's dietary preferences.
4.2Postbiotic supplements in children and adolescents: dose optimization for SCFAs and safety of targeted metabolite formulations
Dysfunction of the gut microbiota–immune–metabolic axis is an important component of childhood obesity pathophysiology, rather than a single main driver. Given the special metabolic flexibility in pediatric populations, postbiotic interventions need to fit developmental characteristics. They should not simply copy treatment plans used for adults. Children with obesity have been reported in some studies to show altered abundances of SCFA-producing bacteria, which may affect SCFA-related metabolic and immune signaling. For this reason, supplementary SCFA blends are designed to adjust SCFA availability and support GPR41/43-related regulation of adipogenesis, inflammation, and gut hormone signaling, rather than as interventions that directly rebuild host signaling. These blends are hypothesized to mainly affect energy-sensing pathways within the gut–brain axis. For instance, inulin can regulate microbial metabolites and has been associated with changes in neural activity, neurotransmitter metabolism, and eating behavior, although these associations are preliminary and derived from a limited number of observational studies (Li S. et al., 2025; Andriyas et al., 2025). A stratified dosing strategy has been proposed. This strategy divides patients into three levels based on BMI and insulin resistance: baseline regulation, metabolic correction, and homeostasis maintenance. This approach allows personalized dose adjustment through real-time monitoring (Luzzi et al., 2024). Safety considerations are also important. Encapsulation technologies can reduce mucosal irritation related to SCFAs, and long-term effects on growth hormone secretion have been reported (Granato et al., 2025). Pediatric products also need to solve problems such as poor taste and low delivery efficiency. They should start from low doses and then increase gradually (Basuray et al., 2024). The proportion of acetate, propionate, and butyrate should be adjusted according to treatment goals, such as improving insulin sensitivity. Additionally, the combined efficacy of SCFA supplements with dietary modification and physical activity still needs further confirmation (Cho, 2021; Lee et al., 2023; Islam et al., 2023).
Apart from SCFAs, supplementation with specific metabolite-based postbiotics may offer a theoretical advantage over live probiotics by circumventing colonization instability and directly providing defined functional compounds. Microbe-derived IPA has anti-obesity effects by regulating intestinal immunity (Jiang et al., 2025). 4-HPAA, whose levels are lower in obese children, shows promising effects in limiting body weight gain (Li Q. R. et al., 2025). Research on Fusobacterium mortiferum and its metabolite 5-aminovaleric acid has improved our understanding of how microbial metabolites influence metabolic health (Deng et al., 2025). Tryptophan-related metabolites are associated with cardiometabolic risk indicators in adolescents. This supports their value in risk stratification and targeted intervention (Rivera et al., 2025). Conversely, TMAO and its precursors are closely related to childhood obesity. This suggests that interventions should not only add beneficial metabolites but also reduce the production of harmful ones (Li et al., 2025). Multi-omics analyses also support these strategies by showing links between pediatric gut microbiota and different lipidomic profiles or newly identified microbial metabolites. This helps identify possible therapeutic targets (Wei et al., 2023; Mora-Godínez et al., 2025; Du et al., 2025). Although postbiotic approaches are mechanistically attractive, they remain predominantly at the preclinical or early-phase clinical stage; given that children's metabolic systems are still developing, rigorous dose-finding studies and long-term safety evaluations in pediatric populations are urgently needed before clinical translation (Wu et al., 2025; Fahim et al., 2025). These longitudinal studies should clarify their effects on physical growth and development, avoid disruption of endogenous metabolic pathways, and confirm whether this type of supplementation is reasonable for young populations (Solito et al., 2021).
4.6Current technical limitations and research bottlenecks in gut microbiota and metabolite studies
Although research on the gut microbiome and metabolites was expanded rapidly, several methodological challenges were identified as core bottlenecks that limited the interpretation and reproducibility of study results. First, dietary composition was confirmed as a primary confounding factor, as total energy intake, fiber content, ultra-processed food consumption, and dietary patterns were verified to reshape microbial composition and metabolite levels (Verduci et al., 2021a; Bagheri et al., 2022; Zheng et al., 2025). Furthermore, variables—including physical activity, sleep rhythms, antibiotic and other medication use, pubertal development, and early-life environmental factors —were observed to exert pressure on the microbiota-metabolite profile independently of disease status (Barata et al., 2025; Celik and Yesildemir, 2025; Chu et al., 2025). Second, heterogeneity across studies was attributed to differences in demographic characteristics, such as age, geographic region, obesity criteria, and comorbidities, as well as experimental protocols, including sampling, preservation, sequencing platforms, and bioinformatics pipelines; batch effects were induced by the lack of standardized operations, and contradictory conclusions were generated (Gawlik et al., 2021; Liu et al., 2025; He et al., 2025). Third, causal inference was constrained by study design; observational or cross-sectional designs were employed, and the establishment of temporal causality was hindered by the scarcity of long-term longitudinal cohorts (He et al., 2025; Pan et al., 2026). In mechanistic validation, differences in immune-metabolic programming between species and off-target effects following microbiota transplantation were noted in animal models (Chen et al., 2022; DeLeon et al., 2025; Jeong et al., 2024). In clinical translation, defects—including insufficient sample sizes in randomized controlled trials, the absence of baseline microbiome stratification, and the lack of long-term safety assessments for fecal microbiota transplantation in adolescents—were recorded (Pastor-Villaescusa et al., 2021; Fatahi et al., 2025; Wang et al., 2025). Standardized sampling, integrated multi-omics research, large-scale longitudinal birth cohorts, and cross-regional collaborations were identified as pathways for future research, and causal inference was strengthened to facilitate the transition from correlation-based descriptions to the identification of evidence chains with clinical translational value (Lin et al., 2025; Shi et al., 2025; Suárez-Cortés et al., 2025).
5Summary and future perspectives
Childhood and adolescent obesity develops from the combined effects of gut dysbiosis, metabolic reprogramming, and chronic low-grade inflammation during key developmental periods. It does not result only from simple energy imbalance (Cho, 2023; Mindru et al., 2025). Gut microbial metabolites should be viewed as a heterogeneous group of candidate mediators rather than as equivalent components with identical biological roles or evidence strength. SCFAs have relatively strong mechanistic support for effects on epithelial barrier integrity, gut hormone secretion, immune regulation, and energy metabolism (Fiore et al., 2022; Li S. et al., 2025). In contrast, indole derivatives and secondary bile acids represent emerging immune-metabolic signaling candidates whose roles are mediated mainly through AHR- and FXR/TGR5-related pathways, but their direct pediatric therapeutic validation remains limited (Giannini et al., 2022; Rivera et al., 2025). 4-HPAA is a promising obesity-associated microbial metabolite, but current evidence is still based mainly on observational associations and experimental validation rather than robust pediatric intervention data (Li Q. R. et al., 2025). Therefore, these metabolites should not be interpreted as having the same level of evidence or the same therapeutic maturity. Collectively, these metabolites affect metabolic and immune balance through a multi-node network that connects dietary substrates, microbiota, metabolites, immune cells, and metabolic organs (Zhou et al., 2023; Jiang et al., 2025; Zhang and Dang, 2022). Figure 6 shows our integrated “dietary substrate–gut microbiota–metabolites–immune cells–metabolic organs” framework. This framework highlights multi-level signaling pathways and feedback loops from environmental input to host response and provides a systematic view of disease development and intervention targets.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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